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Matthews shares 25-year pursuit of a biochemical mystery in Russel Lecture

Rowena G. Matthews, the 2003 Henry Russel lecturer, has been doing bold, creative biochemistry research since the early 1960s at U-M. But it's only been in the last decade that her findings have made her famous.
Matthews (Photo by Martin Vloet, U-M Photo Services)

"I'd like to thank the NIH (National Institutes of Health) for funding this work when we really didn't know that it had any human health relevance," she said toward the end of the 2003 Henry Russel Lecture she delivered in the Michigan League ballroom March 11.

Starting with Vitamin A in the Harvard lab of future Nobel Prize winner George Wald as an undergraduate, Matthews moved on to Vitamin B2 as a graduate student at Michigan. Here, she studied under the late Vincent Massey, who was a Russel lecturer in 1995.

As a chemist, Matthews' interest was in the role vitamins play in helping to catalyze chemical reactions in living cells. These chemicals are critical for life, but we can't make them ourselves; we must get them from our diet, she explained.

She gravitated toward a particular nutrient, folate, or folic acid, which was known to work with an enzyme with an impossibly long name. This enzyme, methylenetetrahydorofolate reductase (or MTHFR for short) is important for the conversion of homocysteine to methionine, an essential component for the synthesis of human proteins.

Starting in 1978, shortly after joining the U-M faculty as a research investigator in biophysics, Matthews and colleagues began a 25-year pursuit of the intricacies of the chemical structures and functions of MTHFR and folate.

Matthews' slides during this tale showed just what sort of scientist she is, moving seamlessly from ball-and-stick chemistry to the ribbon diagrams of structural biology, and on to crystallography, electrophoresis and comparisons of gene sequence.

In 1995, just as Matthews and McGill University geneticist Rima Rozen had identified a gene for the enzyme MTHFR, cardiologists had begun discussing an apparent link between blood homocysteine levels and heart disease.

Matthews knew that "our enzyme," MTHFR, was at least one of the proteins involved in managing blood homocysteine levels. It wasn't long before she and Rozen had found a single-nucleotide difference in the genes of some people that apparently affected their ability to make MTHFR. Indeed, this tiny polymorphism was found to correlate with varying levels of homocysteine and folate. Humans with the variant on both chromosomes had elevated levels of homocysteine, particularly if their folate intake was low.

Matthews and U-M biochemist Martha Ludwig went on to show how, structurally, the one-basepair difference resulted in a form of MTHFR that wouldn't function as it should. People carrying two copies of this allele have a particular need for folate to keep their homocysteine in check.

A few years ago, the U.S. Department of Agriculture began requiring folic acid supplements in grain products. Since then, there has been an average drop of 22 percent in the homocysteine levels of Americans, she said. Matthews, along with "almost everyone I know in the homocysteine field," takes vitamin supplements with folate.

The Russel Lecture is the highest award U-M can bestow on a senior faculty member, and it is given in recognition of exceptional research and teaching. Matthews is the G. Robert Greenberg Distinguished University Professor of Biological Chemistry, and a Senior Research Scientist in the Life Sciences Institute and the Biophysics Research Division. Last year, she was elected a member of the National Academy of Sciences.

Nominators for Matthews cited her "first-rate intellectual rigor and clarity of purpose," calling her work "comprehensive, comprehensible and important." They said she is "exceptional for the breadth of her scientific and technical ability." Attendees of the Russel lecture also discovered that she gives a great lecture. Matthews' sincere affection and gratitude toward mentors, colleagues and students alike was clearly displayed in a series of slides showing the people she has worked with since coming to Ann Arbor in 1963.

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